11-57598250-T-C

Position:

chr11-57598250-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000062.3(SERPING1):c.-21T>C variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,544,846 control chromosomes in the GnomAD database, including 1,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 93 hom., cov: 31)

Exomes 𝑓: 0.043 ( 1466 hom. )

Consequence

SERPING1
NM_000062.3 splice_region, 5_prime_UTR

Scores

Splicing: ADA: 0.0005334

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.247

Variant links:

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015582442).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0314 (4774/152100) while in subpopulation NFE AF= 0.0484 (3288/67970). AF 95% confidence interval is 0.047. There are 93 homozygotes in gnomad4. There are 2260 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 93 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.-21T>C		splice_region_variant, 5_prime_UTR_variant	2/8	ENST00000278407.9
SERPING1	NM_001032295.2 linkuse as main transcript	c.-21T>C		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.-21T>C		splice_region_variant, 5_prime_UTR_variant	2/8	1	NM_000062.3	P2	P05155-1

Frequencies

GnomAD3 genomes

AF:

0.0314

AC:

4776

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00834

Gnomad AMI

AF:

0.0771

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.0510

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0484

Gnomad OTH

AF:

0.0297

GnomAD3 exomes

AF:

0.0291

AC:

4285

AN:

147346

Hom.:

AF XY:

0.0292

AC XY:

2312

AN XY:

79186

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000921

Gnomad SAS exome

AF:

0.00917

Gnomad FIN exome

AF:

0.0498

Gnomad NFE exome

AF:

0.0467

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0429

AC:

59761

AN:

1392746

Hom.:

1466

Cov.:

AF XY:

0.0419

AC XY:

28767

AN XY:

686004

show subpopulations

Gnomad4 AFR exome

AF:

0.00745

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.0208

Gnomad4 EAS exome

AF:

0.0000559

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.0537

Gnomad4 NFE exome

AF:

0.0491

Gnomad4 OTH exome

AF:

0.0351

GnomAD4 genome

AF:

0.0314

AC:

4774

AN:

152100

Hom.:

Cov.:

AF XY:

0.0304

AC XY:

2260

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00831

Gnomad4 AMR

AF:

0.0225

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000584

Gnomad4 SAS

AF:

0.00766

Gnomad4 FIN

AF:

0.0510

Gnomad4 NFE

AF:

0.0484

Gnomad4 OTH

AF:

0.0294

Alfa

AF:

0.0436

Hom.:

192

Bravo

AF:

0.0292

ESP6500AA

AF:

0.00671

AC:

ESP6500EA

AF:

0.0329

AC:

264

ExAC

AF:

0.0159

AC:

1662

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2019	This variant is associated with the following publications: (PMID: 16470590, 27884173, 29676077, 27116602, 23437219, 18586324, 20804470, 8755917) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

Hereditary angioedema type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.60

MutationTaster

Benign

1.0

D;D;D;D;N

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.032

ClinPred

0.012

GERP RS

-0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over